DNAAF1 – Primary Ciliary Dyskinesia

DNAAF1 encodes a cytoplasmic dynein assembly factor essential for outer and inner dynein arm formation in motile cilia. Biallelic pathogenic variants in DNAAF1 result in impaired ciliary motility and the autosomal recessive (AR) disorder primary ciliary dyskinesia (PCD). Clinical presentations include bronchiectasis, low nasal nitric oxide, situs anomalies, and recurrent respiratory infections. Electron microscopy in several patients reveals combined outer and inner dynein arm defects, confirming the ultrastructural hallmark of PCD.

Genetic evidence comprises at least 10 unrelated probands: a consanguineous Japanese case report (1)[PMID:38432987], four families with DNAAF1 variants including homozygous p.Leu191Phe in multiple PCD pedigrees (≥4 probands)[PMID:29228333], two Chinese Han probands with novel DNAAF1 LoF alleles[PMID:33174003], and three Korean pediatric patients harboring DNAAF1 mutations[PMID:37957793]. Variants span missense (e.g., c.571C>T (p.Leu191Phe)), canonical splice (c.124+1G>C), and frameshift/stop-gain alleles, all segregating in AR fashion.

Segregation was documented in siblings: two affected siblings with isolated heterotaxy carry homozygous c.571C>T (p.Leu191Phe), segregating perfectly with DNAAF1 alleles in one family([PMID:29228333]), further supporting causality under AR inheritance.

Functional studies demonstrate that wild-type human DNAAF1 rescues heart looping in dnaaf1-null zebrafish but the p.Leu191Phe variant does not, confirming conserved pathogenicity([PMID:29228333]). Mouse Dnaaf1 splice‐site mutants display hydrocephalus, laterality defects, sinusitis, and early lethality, recapitulating motile cilia dysfunction([PMID:27261005]).

Additional cellular assays show frameshift and stop-gain DNAAF1 mutants abolish dynein arm preassembly and reduce protein expression. NanoString analysis of neural tube defect (NTD) samples indicates that DNAAF1 LoF alleles can alter expression of neural tube closure genes, suggesting pleiotropic effects in development([PMID:27543293]).

Overall, the collective genetic and experimental data support a Strong clinical validity for DNAAF1 in AR PCD. There are no reported conflicting studies. DNAAF1 sequencing should be included in PCD diagnostic panels, and identification of DNAAF1 variants informs prognosis, management, and genetic counseling.

References

• Internal medicine (Tokyo, Japan) • 2024 • Primary Ciliary Dyskinesia Caused by Homozygous DNAAF1 Mutations Resulting from a Consanguineous Marriage: A Case Report from Japan. PMID:38432987
• Human molecular genetics • 2018 • DNAAF1 links heart laterality with the AAA+ ATPase RUVBL1 and ciliary intraflagellar transport. PMID:29228333
• Molecular medicine reports • 2020 • Novel dynein axonemal assembly factor 1 mutations identified using whole‐exome sequencing in patients with primary ciliary dyskinesi PMID:33174003
• Allergy, asthma & immunology research • 2023 • Clinical Manifestations and Genotype of Primary Ciliary Dyskinesia Diagnosed in Korea: Multicenter Study. PMID:37957793
• G3 (Bethesda, Md.) • 2016 • Mutations in Dnaaf1 and Lrrc48 Cause Hydrocephalus, Laterality Defects, and Sinusitis in Mice. PMID:27261005
• G3 (Bethesda, Md.) • 2016 • Mutations in the Motile Cilia Gene DNAAF1 Are Associated with Neural Tube Defects in Humans. PMID:27543293

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